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Elucidating the Role of Tumor Macrophages and Mesenchymal Cells during Breast Cancer Metastasis

Thies, Katie A.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1492436944731976

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Improvements have been made in the diagnosis and treatment of patients with breast cancer, but for those with advanced, metastatic disease the outlook is not nearly as promising. Over the past several years, studies have highlighted a role for the tumor microenvironment in contributing to metastatic progression. Both cells of the myeloid lineage as well as mesenchymal cells, namely fibroblasts and pericytes, are known to be involved in several steps of the metastatic cascade. However, the molecular mechanisms by which these stromal cells mediate metastasis remain unclear. Our efforts have focused on two receptor tyrosine kinases: Colony Stimulating Factor-1 Receptor (CSF1R) and Platelet Derived Growth Factor Receptor (PDGFR), which are expressed by macrophages and mesenchymal cells respectively. The myeloid survival factor, CSF1, is produced by cancer cells and is known to promote macrophage recruitment to the tumor. However, the specific regulatory networks activated by CSF1 in tumor-associated macrophages during metastasis have not been delineated. Here, we demonstrate the presence of a CSF1-driven oncogenic microRNA expression signature, including miR-21 and miR-29a, in tumor-associated macrophages. Upon analyzing CSF1R+ cells isolated from patient blood, we found miR-21 and miR-29a expression correlate with increased metastatic tumor burden. With CSF1R inhibitors being used in clinical trials, microRNA expression might serve as a read-out for therapeutic efficacy. In a second, independent study, we evaluated the role of PDGF signaling in metastatic breast cancer progression. PDGF receptors are expressed in fibroblasts and pericytes while PDGF ligands are often expressed in cancer cells and the tumor-associated endothelium. Still, little has been done to understand the role of PDGF signaling in breast cancer initiation, progression and metastasis. We established a transgenic knock-in mouse model that expresses constitutively active PDGFRß in the mesenchymal lineage (e.g. fibroblasts and pericytes) and using this model, performed experimental metastasis assays to test the hypothesis that stromal PDGFRß signaling promotes metastatic progression of breast cancer. To our knowledge, this is the first example where genetic manipulation of the stroma leads to an increased incidence of breast cancer brain metastases. Furthermore, this study highlights a role for stromal PDGFRß activation in metastasis to the brain.
Michael Ostrowski, Ph.D. (Advisor)
Balveen Kaur, Ph.D. (Committee Member)
Christin Burd, Ph.D. (Committee Member)
Thomas Ludwig, Ph.D. (Committee Member)
191 p.
Molecular Biology
Breast Cancer; Metastasis; Tumor-Associated Macrophages; Fibroblasts; Pericytes

Recommended Citations

Citations

  • Thies, K. A. (2017). Elucidating the Role of Tumor Macrophages and Mesenchymal Cells during Breast Cancer Metastasis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492436944731976

    APA Style (7th edition)

  • Thies, Katie. Elucidating the Role of Tumor Macrophages and Mesenchymal Cells during Breast Cancer Metastasis. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1492436944731976.

    MLA Style (8th edition)

  • Thies, Katie. "Elucidating the Role of Tumor Macrophages and Mesenchymal Cells during Breast Cancer Metastasis." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492436944731976

    Chicago Manual of Style (17th edition)

osu1492436944731976
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© 2017, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.